Ptp1b inhibitors, synthesis thereof and application thereof in preparation of medicaments for treating type 2 diabetes mellitus

ABSTRACT

The present invention relates to chemical total synthesis methods of six novel protein tyrosine phosphatase-1B (PTP1B) inhibitors and application of the inhibitors in the preparation of medicaments for treating type 2 diabetes mellitus (T2DM). The PTP1B inhibitors use one or more of the six compounds represented by the structural formulae 1, 2, 3, 4, 5 and 6, as active components. The compounds can enhance the sensitivity of an insulin receptor by inhibiting the activity of PTP1B, thereby having a favorable therapeutic effect on insulin-resistant T2DM.

FIELD OF THE INVENTION

This invention is in the field of biological medicine and specificallyrelates to the preparation, pharmacological activities and applicationof six bromophenol compounds, including

(2′-bromo-6′-(dibromomethyl)-3′,4′-dimethoxyphenyl)-(2,3-dibromo-4,5-dimethoxyphenyl)-methanone (1),

3,4-dibromo-5-[2′-bromo-3′,4′-dihydroxy-6′-(propoxymethyl)-benzyl]-benzene-1,2-diol(2),3,4-dibromo-5-[2′-bromo-3′,4′-dihydroxy-6′-(isopropoxymethyl)-benzyl]-benzene-1,2-diol(3),3,4-dibromo-5-[2′-bromo-6′-(butoxymethyl)-3′,4′-dihydroxy-benzyl]-benzene-1,2-diol(4),3,4-dibromo-5-[2′-bromo-3′,4′-dihydroxy-6′-(isobutoxymethyl)-benzyl]-benzene-1,2-diol(5),2,3-dibromo-1-[2′-bromo-6′-(2″-bromo-4″,5″-dimethoxybenzyl)-3′,4′-dimethoxybenzyl]-4,5-dimethoxybenzene(6). All of the bromophenol derivatives are intended for treating type 2diabetes mellitus as insulin sensitizers.

BACKGROUND OF THE INVENTION

Type 2 diabetes mellitus (T2DM) is a chronic endocrine and metabolicdisorder. To date, medications for T2DM include biguanides,sulfonylureas, α-glucosidase inhibitors and thiazolidinediones. However,there are many drawbacks in their clinical use, because that the drugsare designed for symptoms not for disease target. Consequently, moreefficient and safe drugs with reasonable prices are badly needed.

Insulin resistance is the key factor of T2DM. Studies demonstrated thatprotein tyrosine phosphatase 1B (PTP1B) has emerged as a noveltherapeutic strategy for the treatments of type 2 diabetes mellitus.PTP1B plays an important role in the negative regulation of insulinsignal transduction pathways. Accumulating evidences indicated thatPTP1B inhibitors increased the level of phosphorylation of the insulinreceptor and its substrate, and promote glucose transportertranslocation and increased glucose uptake in insulin-sensitive cells.PTP1B inhibitor played insulin analogues and insulin-sensitizing agent.Knockout the PTP1B gene or inhibition of PTP1B protein and mRNAexpression with antisense oligonucleotide (ASO), not only cansignificantly improve the insulin sensitivity of the test mice, but alsosignificantly reduce the risk of obesity patients. Gold-stein et al.showed that the expression of PTP1B and LAR PTP in insulin targettissues of patients with insulin resistance are increased, and theincrease block the activation of the insulin receptor tyrosine andinsulin signal transduction. P387L Is a missense mutation of PTP1B,Echwald et al confirmed that the gene mutation frequency was 1.4% inpatients with type 2 diabetes, while only 0.5% in the control group. itis speculated that the mutation in related with type 2 diabetes.Investigation of the role of PTP1B using an antisense oligonucleotide(ASO) in ob/ob mice suggest that while PTP1B expression in liver, fatand skeletal muscle down, blood glucose of ob/ob mice returned tonormal, and indicators of glucose metabolism also became normal.Additionally, insulin clamp experiments showed that the liver andperipheral tissues of diabetic mice enhanced insulin sensitivity. Theseresults confirm the negative regulatory role of PTP1B in insulin signaltransduction, and its increased activity may be a causative factor forinsulin resistance and insulin receptor signaling impaired. Based onthese data, PTP1B has already been considered as one of the bestvalidated biological targets for T2DM.

Reported PTP1B inhibitors include: (1) Peptide PTP1B inhibitors, whichcontain mimetics of pTyr, have high affinity with PTP1B. But thecompounds have poor chemical and biological stability. (2)Naphthnoquinone, inhibited PTP1B activity by modification of the activesites of PTPase. (3) Thiazolidinedione, improve blood glucose control byenhancing insulin sensitivities to the target organs. Representativecompounds include ciglitazone, troglitazone and rosiglitazone. However,ciglitazone has been withdrawn from market due to severe hepatotoxicity.(4) Benzo[b]naphthol[2,3-d]furans and thiophenes, these compounds aredesigned based on benzbromarone (PTP1B inhibitor, IC₅₀=26 μM) andexhibited good hypoglycemic activity in mice. Unfortunately, highlynegative charged, the poor cell permeability and low bioavailability ofthese compounds have limited their application for the development ofeffective drugs. We have discovered a series of brominated marinenatural products from red algae with potent PTP1B inhibition andsynthesized their derivatives

(2′-bromo-6′-(dibromomethyl)-3′,4′-dimethoxyphenyl)-(2,3-dibromo-4,5-dimethoxyphenyl)-methanone (1),3,4-dibromo-5-[2′-bromo-3′,4′-dihydroxy-6′-(propoxymethyl)-benzyl]-benzene-1,2-diol(2),3,4-dibromo-5-[2′-bromo-3′,4′-dihydroxy-6′-(isopropoxymethyl)-benzyl]-benzene-1,2-diol(3),3,4-dibromo-5-[2′-bromo-6′-(butoxymethyl)-3′,4′-dihydroxy-benzyl]-benzene-1,2-diol(4),3,4-dibromo-5-[2′-bromo-3′,4′-dihydroxy-6′-(isobutoxymethyl)-benzyl]-benzene-1,2-diol(5),2,3-dibromo-1-[2′-bromo-6′-(2″-bromo-4″,5″-dimethoxybenzyl)-3′,4′-dimethoxybenzyl]-4,5-dimethoxybenzene(6).

SUMMARY OF INVENTION

This invention provides six novel PTP1B inhibitors, which can be usedfor treatment of T2DM by inhibiting PTP1B and enhancing sensitivity ofinsulin receptor.

The structures of the six compounds are as follows:

1.(2′-bromo-6′-(dibromomethyl)-3′,4′-dimethoxyphenyl)-(2,3-dibromo-4,5-dimethoxyphenyl)-methanone;

2.3,4-dibromo-5-[2′-bromo-3′,4′-dihydroxy-6′-(propoxymethyl)-benzyl]-benzene-1,2-diol;

3.3,4-dibromo-5-[2′-bromo-3′,4′-dihydroxy-6′-(isopropoxymethyl)-benzyl]-benzene-1,2-diol;

4.3,4-dibromo-5-[2′-bromo-6′-(butoxymethyl)-3′,4′-dihydroxy-benzyl]-benzene-1,2-diol;

5.3,4-dibromo-5-[2′-bromo-3′,4′-dihydroxy-6′-(isobutoxymethyl)-benzyl]-benzene-1,2-diol;

6.2,3-dibromo-1-[2′-bromo-6′-(2″-bromo-4″,5″-dimethoxybenzyl)-3′,4′-dimethoxybenzyl]-4,5-dimethoxybenzene.

DETAILED DESCRIPTIONS OF THE INVENTION

Scheme 1 shows the preparation of

(2′-bromo-6′-(dibromomethyl)-3′,4′-dimethoxyphenyl)-(2,3-dibromo-4,5-dimethoxyphenyl)-methanone (1).

Scheme 1 (a) bromine and compound 7 (molar ratio is 1:1), MeOH, ice bathcondition; (b) Methyl iodide and compound 8 (molar ratio is 1:1˜1:1.5),K₂CO₃, DMF as solvent, room temperature; (c) a solution of compound 9 indiglycol (mass concentration of compound 9: 10˜15%), mass concentration80% hydrazine hydrate solution, KOH, 110˜120° C.; (d) bromine andcompound 9 (molar ratio is 2:1˜3:1), acetic acid, 60˜70° C.; (e) KMnO₄,water, 90° C.; (f) Trifluoroacetic anhydride, H₃PO₄, 0˜60° C.; (g)N-Bromosuccinimide, AIBN, CCl₄, hυ.

Synthesis and Characterization of 5-Bromo-Vanilline (8)

Under ice bath condition, to a solution of vanilline in MeOH (massratio, vanilline: MeOH=1:6˜1:7) was added dropwise bromine (mole ratio,vanilline: bromine=1:1) within 1-2 hours. The mixture was warmed to roomtemperature and stirred for further 0.5-1 hour. The mixture was cooledto 0° C. and added ice water (volume ratio, H₂O:MeOH=1:2˜1:3) within20-30 min, then precipitate was separated out. The mixture was stirredfor further 15-30 min. The precipitate was filtered and washed with icewater and dried to give white solid. Spectrum analysis verified thecompound is 5-Br-vanillin.

The physical and chemical properties of 5-Br-vanillin:m.p. 160-162° C.¹H-NMR (500 MHz, CDCl₃) δ: 9.78 (s, 1H), 7.64 (d, J=1.65 Hz, 1H), 7.36(d, J=1.65 Hz, 2H), 3.98 (s, 3H); ¹³C-NMR (125 MHz, CDCl₃) δ: 189.5(CHO), 148.9 (C), 147.7 (C), 130.1, 130.0 (C), 108.2 (C), 108.1 (CH),56.6 (CH₃).

Synthesis and Characterization of 5-bromo-Veratraldehyde (9)

To a suspension of 5-Br-vanillin and K2CO3 in DMF (mass ratio, K2CO3:DMF=1:8˜1:12) was added dropwise CH3I (mole ratio, 5-Br-vanillin:CH3I=1:1˜1:1.5) at room temperature. After stirring for 24 h, brine (18-22%)was added to quench the reaction. The mixture was extracted withtent-butyl methyl ether three times. The organic layer was collected,washed with brine (18-22%), dried over anhydrous Na₂SO₄ and concentratedin vacuo to give white solid. Spectrum analysis verified the compound is5-bromo-veratraldehyde.

The physical and chemical properties: m.p. 60-62° C. ¹H-NMR (500 MHz,CDCl₃) δ: 9.84 (s, 1H), 7.64 (s, 1H), 7.38 (s, 1H), 3.94 (s, 3H), 3.93(s, 3H); ¹³C-NMR (125 MHz, CDCl₃) δ: 189.7 (CHO), 154.2 (C), 151.8 (C),133.1 (C), 128.7 (CH), 117.9 (CH), 110.2 (C), 60.8 (CH₃), 56.2 (CH₃).

Synthesis and Characterization of 5-bromo-3,4-dimethoxy-methylbenzene(10)

To a solution of 5-bromo-veratraldehyde in diglycol was added 80%hydrazine hydrate (mole ratio,3-bromo-4,5-dimethoxybenzaldehyde:hydrazine hydrate=1:1˜1:1.5) at roomtemperature. TLC was used to monitor the reaction. Then KOH (8-12%) wasadded. The mixture was heated to 110-120° C. and stirred for 2-3 hours.After cooling, the resulting mixture was poured into water, andextracted with CH₂Cl₂ for three times. The organic lay was collected,washed with 1 mol/L HCl, dried over anhydrous MgSO₄ and concentrated invacuo to give colorless oil. Spectrum analysis verified the compound is5-bromo-3,4-dimethoxy-methylbenzene.

The physical and chemical properties:¹H-NMR (500 MHz, CDCl₃) δ: 6.94 (s,1H), 6.65 (s, 1H), 3.84 (s, 3H), 3.82 (s, 3H), 2.28 (s, 3H); ¹³C-NMR(125 MHz, CDCl₃) δ: 153.3 (C), 144.1 (C), 135.1 (C), 124.8 (CH), 117.1(C), 112.5 (CH), 60.4 (CH₃), 55.9 (CH₃), 21.0 (CH₃).

Synthesis and Characterization of 5,6-dibromo-veratraldehyde (11)

At room temperature, to a solution of 3-bromo-4,5-dimethoxybenzaldehydein AcOH (mass concentration: 10-15%) was added dropwise bromine (moleratio, bromine:3-bromo-4,5-dimethoxybenzaldehyde=2:1˜3:1) and catalystiron powder. The mixture was heated at 60-70° C. and stirred for 4-6hours. After cooling to room temperature, the iron powder was filteredand the filtrate was removed in vacuo. The residue was redissolved inCHCl₃, and washed with 5% Na₂SO₃ for two times. The organic lay wascollected, and concentrated in vacuo. The residue was recrystallized inacetone to give white needle crystal. Spectrum analysis verified thecompound is 5,6-dibromo-veratraldehyde.

The physical and chemical properties: m.p. 128-130° C. ¹H-NMR (500 MHz,CDCl₃) δ: 10.27 (s, 1H), 7.48 (s, 1H), 3.94 (s, 3H), 3.92 (s, 3H);¹³C-NMR (125 MHz, CDCl₃) δ: 191.5 (CHO), 152.8 (C), 131.0 (C), 122.8(C), 121.9 (C), 111.7 (CH), 60.8 (CH₃), 56.3 (CH₃).

Synthesis and Characterization of 5,6-dibromo-veratric Acid (12)

NaHCO₃, 5,6-dibromo-veratraldehyde and H₂O were successively placed in athree-necked round bottom flask. The suspension was heated to 90° C. andadded KMnO₄ (mole ratio, KMnO₄:2,3-dibromo-4,5-dimethoxybenzaldehyde=1:1˜1:1.5) in three portions. TLCwas used to monitor the reaction. The MnO₂ was filtered and the filtratewas acidified. The white precipitate was filtered and dried to givewhite solid. Spectrum analysis verified the compound is5,6-dibromo-veratric acid.

The physical and chemical properties: m.p. 180-181° C.; ¹H NMR (500 MHz,CD₃OCD₃): δ 7.39 (s, 1H, H-2), 3.90 (s, 3H, H-8), 3.87 (s, 3H, H-9); ¹³CNMR (125 MHz, CD₃OCD₃): δ 169.2 (C-7), 153.6 (C-4), 150.9 (C-3), 132.8(C-1), 127.5 (C-6), 123.8 (C-5), 114.5 (C-2), 60.9 (C-8), 56.9 (C-9).

Synthesis and characterization of

(2-bromo-3,4-dimethoxy-6-methylphenyl)-(2,3-dibromo-4,5-dimethoxyphenyl)-methanone(13)

Under ice bath condition, 5,6-dibromo-veratric acid was placed in athree-necked round bottom flask and dissolved in TFAA. To the stirredsolution was added 85% H₃PO₄ and 1-bromo-2,3-dimethoxy-5-methylbenzene(mole ratio, 2,3-dibromo-4,5-dimethoxybenzoic acid:1-bromo-2,3-dimethoxy-5-methylbenzene=1:1). The mixture was heated to60° C. and TLC was used to monitor the reaction. The mixture was pouredinto crushed ice and extracted with CHCl₃ for three times. The organiclayer was collected and concentrated in vacuo. The residue wasrecrystallized in EtOH to give white crystal. Spectrum analysis verifiedthe compound is(2-bromo-3,4-dimethoxy-6-methylphenyl)-(2,3-dibromo-4,5-dimethoxyphenyl)-methanone.

The physical and chemical properties: m.p. 86-88° C.; ¹H NMR (500 MHz,CDCl₃): δ 7.16 (s, 1H, H-6), 6.74 (s, 1H, H-5′), 3.91 (s, 3H, H-9), 3.90(s, 3H, H-11), 3.81 (s, 3H, H-10), 3.79 (s, 3H, H-12), 2.22 (s, 3H,H-8); ¹³C NMR (125 MHz, CDCl₃): δ 194.2 (C-7), 154.0 (C-4), 152.0(C-4′), 150.8 (C-5), 144.6 (C-3′), 135.7 (C-1), 133.7 (C-1′), 133.0(C-6′), 124.3 (C-2), 116.3 (C-2′), 115.5 (C-3), 115.1 (C-6), 113.8(C-5′), 60.6 (C-9,11), 56.3 (C-10), 56.0 (C-12), 20.2 (C-8).

Synthesis and characterization of

(2-bromo-6-(dibromomethyl)-3,4-dimethoxyphenyl)-(2,3-dibromo-4,5-dimethoxyphenyl)-methanone(1)

(2-bromo-3,4-dimethoxy-6-methylphenyl)-(2,3-dibromo-4,5-dimethoxyphenyl)-methanone and catalyst AIBN was placed in a three-necked round bottom flask, anddissolved in CCl₄. Under hυ condition, to the solution was added NBSwith stirring. TLC was used to monitor the reaction. The precipitate wasfiltered off and the filtrate was removed in vacuo to produce a brownishresidue. The residue was purified by chromatography to give white solid.Spectrum analysis verified the compound is(2-bromo-6-(dibromomethyl)-3,4-dimethoxyphenyl)-(2,3-dibromo-4,5-dimethoxyphenyl)-methanone.

The physical and chemical properties: m.p. 166-169° C.; ¹H NMR (500 MHz,CDCl₃): δ 7.58 (s, 1H), 7.07 (s, 1H), 6.66 (s, 1H), 4.03 (s, 3H), 3.93(s, 3H), 3.87 (s, 3H), 3.78 (s, 3H); ¹³C NMR (125 MHz, CDCl₃): δ192.8(CO), 155.1, 152.0, 151.2, 147.6, 137.4, 135.2, 129.2, 124.7, 116.8,115.1, 114.4, 113.5, 60.8 (2×CH₃), 56.4 (2×CH₃), 36.7 (CHBr₂); HRMS:[M+H]⁺ calcd for C₁₈H₁₆O₅Br₅: 706.6915, found: 706.6882.

Scheme 2 shows the preparation of

3,4-dibromo-5-[2′-bromo-3′,4′-dihydroxy-6′-(propoxymethyl)-benzyl]-benzene-1,2-diol(2),3,4-dibromo-5-[2′-bromo-3′,4′-dihydroxy-6′-(isopropoxymethyl)-benzyl]-benzene-1,2-diol(3),3,4-dibromo-5-[2′-bromo-6′-(butoxymethyl)-3′,4′-dihydroxy-benzyl]-benzene-1,2-diol(4),3,4-dibromo-5-[2′-bromo-3′,4′-dihydroxy-6′-(isobutoxymethyl)-benzyl]-benzene-1,2-diol(5)

Scheme 2 (h) NaBH₄, MeOH, 0° C.; (i) AlCl₃, CH₂Cl₂, 0° C.; (j)N-Bromosuccinimide, CCl₄, hυ; H₂O, dioxane, reflux; (k) BBr₃, CH₂Cl₂, 0°C.; H₃PO₄, corresponding alcohol, 70˜80° C.

Synthesis and Characterization of5,6-dibromo-3,4-dimethoxy-phenyl-methanol

Under ice bath condition, to a stirred solution of5,6-dibromo-veratraldehyde in MeOH was added NaBH₄ (mole ratio, NaBH₄:5,6-dibromo-veratraldehyde=1:4˜1:3). TLC was used to monitor thereaction. 10% HCl was added into the reaction to acidified pH=5-6. MeOHwas evaporated and the residue was extracted with CH₂Cl₂. The organiclay was collected, dried over anhydrous MgSO₄ and concentrated in vacuoto give white solid. Spectrum analysis verified the compound is5,6-dibromo-3,4-dimethoxy-phenyl-methanol.

The physical and chemical properties: m.p. 91-93° C. ¹H-NMR (500 MHz,CDCl₃) δ: 7.01 (s, 1H), 4.71 (s, 2H), 3.88 (s, 3H), 3.84 (s, 3H);¹³C-NMR (125 MHz, CDCl₃) δ: 152.7 (C), 146.8 (C), 137.3 (C), 121.7 (C),114.9 (C), 111.5 (CH), 65.9 (CH₂), 60.5 (CH₃), 56.2 (CH₃).

Synthesis and characterization of2,3-dibromo-1-(2′-bromo-3′,4′-dimethoxy-6′-methylbenzyl)-4,5-dimethoxybenzene (15)

Under ice bath condition, to a stirred solution of5-bromo-3,4-dimethoxy-methylbenzene and5,6-dibromo-3,4-dimethoxy-phenyl-methanol in CH₂Cl₂ was added AlCl₃(mole ratio,AlCl₃:1-bromo-2,3-dimethoxy-5-methylbenzene:2,3-dibromo-4,5-dimethoxy-phenyl-methanol=1:1:1)in three portions. TLC was used to monitor the reaction. The mixture waspoured into ice water. The organic layer was washed with 3% HCl threetimes, dried over anhydrous MgSO₄ and concentrated in vacuo. The residuewas recrystallized from MeOH to give white solid. Spectrum analysisverified the compound is2,3-dibromo-1-(2′-bromo-3′,4′-dimethoxy-6′-methylbenzyl)-4,5-dimethoxybenzene

The physical and chemical properties: m.p. 114-117° C. ¹H-NMR (500 MHz,CDCl₃) δ: 6.76 (s, 1H), 6.15 (s, 1H), 4.19 (s, 2H), 3.89 (s, 3H), 3.84(s, 3H), 3.81 (s, 3H), 3.56 (s, 3H), 2.17 (s, 3H); ¹³C-NMR (125 MHz,CDCl₃) δ: 152.5 (C), 152.0 (C), 146.1 (C), 144.9 (C), 135.8 (C), 134.3(C), 129.6 (C), 122.1 (C), 121.7 (C), 117.6 (C), 113.8 (CH), 111.7 (CH),60.4 (2×CH₃), 56.1 (CH₃), 56.0 (CH₃), 40.5 (CH₂), 20.6 (CH₃).

Synthesis and characterization of(3-bromo-2-(2′,3′-dibromo-4′,5′-dimethoxybenzyl)-4,5-dimethoxyphenyl)-methanol(16)

Under hυ condition, to a solution of catalyst AIBN or BPO and2,3-dibromo-1-(2′-bromo-3′,4′-dimethoxy-6′-methylbenzyl)-4,5-dimethoxybenzene and in CCl₄ (mass concentration 5˜10%) was added NBS (moleratio, AIBN or BPO:2,3-dibromo-1-(2′-bromo-3′,4′-dimethoxy-6′-methylbenzyl)-4,5-dimethoxybenzene =1:100, NBS:2,3-dibromo-1-(2′-bromo-3′,4′-dimethoxy-6′-methylbenzyl)-4,5-dimethoxybenzene=1.1:1) with stirring. TLC was used to monitor the reaction. Thenhυ stopped. The precipitate was filtered off and the solvent was removedin vacuo to produce a brownish residue. The residue was purified bychromatography eluted with petroleum ether and ethyl acetate (8:1) togive white solid. The white solid (mass concentration 5˜10%) and K₂CO₃(mass concentration 5˜10%) were dissolved in mixture of dixoane and H₂O(volume ratio, 1:1) and the reaction was heated to 90-100° C. TLC wasused to monitor the reaction. The mixture was extracted with CHCl₃. Theorganic lay was collected and concentrated in vacuo to give white solid.Spectrum analysis verified the compound is(3-bromo-2-(2′,3′-dibromo-4′,5′-dimethoxybenzyl)-4,5-dimethoxyphenyl)-methanol.

The physical and chemical properties: m.p. 164-166° C. ¹H-NMR (500 MHz,CDCl₃) δ: 7.09 (s, 1H), 6.14 (s, 1H), 4.52 (s, 2H), 4.22 (s, 2H), 3.91(s, 3H), 3.86 (s, 3H), 3.79 (s, 3H), 3.55 (s, 3H); ¹³C-NMR (125 MHz,CDCl₃) δ: 152.4 (2×C), 146.1 (C), 145.9 (C), 136.6 (C), 135.8 (C), 128.7(C), 122.5 (C), 121.7 (C), 117.4 (C), 111.8 (CH), 111.4 (CH), 63.0(CH₂), 60.4 (2×CH₃), 56.0 (2XCH₃), 39.2 (CH₂).

Synthesis and characterization of

3,4-dibromo-5-(2-bromo-3,4-dihydroxy-6-(propoxymethyl)benzyl)benzene-1,2-diol(2)

Under 0° C. condition, to a solution of(3-bromo-2-(2′,3′-dibromo-4′,5′-dimethoxybenzyl)-4,5-dimethoxyphenyl)-methanolin CH₂Cl₂ was added dropwise BBr₃ (1 mol·L⁻¹ in CH₂Cl₂, mass ratio, BBr₃: compound 8=6:1˜8:1). The reaction mixture stirred over night at roomtemperature. Then the mixture was poured into ice-cold water andextracted with EtOAc for three times. The organic lay was collected, andconcentrated in vacuo. The residue was dissolved in n-propanol and added1˜5 mL 85% H₃PO₄. After refluxing for 10-12 hours, the solvent wasremoved in vacuo. The residue was purified by column chromatographyeluted with petroleum ether and ethyl acetate (8:1) to produce yellowsolid. Spectrum analysis verified the compound is3,4-dibromo-5-(2-bromo-3,4-dihydroxy-6-(propoxymethyl)benzyl)benzene-1,2-diol.The physical and chemical properties: ¹H NMR (500 MHz, DMSO-d₆): δ 9.75(s, 1H), 9.69 (s, 1H), 9.27 (s, 1H), 9.14 (s, 1H), 6.88 (s, 1H), 6.05(s, 1H), 4.17 (s, 2H), 3.99 (s, 2H), 3.26 (t, J=6.52, 2H), 1.14 (m, J=,2H), 0.79 (t, J=7.36, 3H); 13C NMR (125 MHz, DMSO-d₆): δ 144.9 (C),144.3 (C), 142.5 (2×C), 130.5 (C), 129.0 (C), 127.5 (C), 115.4, 114.6(C), 114.3, 113.9 (C), 112.9 (C), 71.2 (CH₂), 70.3 (CH₂), 38.3 (CH₂),22.2 (CH₂), 10.4 (CH₃); EIMS m/z 544/542/540/538[M] ⁺ (1/3/3/1),484/482/480/478 (2/7/7/2), 467/465/463/461 (2/6/6/2), 403/401/399(7/15/7), 322/320 (19/18), 82/80 (42/43), 59 (100); HRMS: [M-HT]⁻calcdfor C₁₇H₁₆O₅ ⁷⁹Br₃:536.8548; found: 536.8570.

Synthesis and characterization of

3,4-dibromo-5-(2-bromo-3,4-dihydroxy-6-(isopropoxymethyl)benzyl)benzene-1,2-diol(3)

Under 0° C. condition, to a solution of(3-bromo-2-(2′,3′-dibromo-4′,5′-dimethoxybenzyl)-4,5-dimethoxyphenyl)-methanolin CH₂Cl₂ was added dropwise BBr₃ (1 mol·L⁻¹ in CH₂Cl₂, mass ratio,BBr₃:compound 8=6:1˜8:1). The reaction mixture stirred over night atroom temperature. Then the mixture was poured into ice-cold water andextracted with EtOAc for three times. The organic lay was collected, andconcentrated in vacuo. The residue was dissolved in iso-propanol andadded 1˜5 mL 85% H₃PO₄. After refluxing for 10-12 hours, the solvent wasremoved in vacuo. The residue was purified by column chromatographyeluted with petroleum ether and ethyl acetate (8:1) to produce yellowsolid. Spectrum analysis verified the compound is3,4-dibromo-5-(2-bromo-3,4-dihydroxy-6-(isopropoxymethyl)benzyl)benzene-1,2-diol.

The physical and chemical properties: ¹H NMR (500 MHz, DMSO-d₆): δ 9.72(s, 1H), 9.69(s, 1H), 9.26 (s, 1H), 9.11 (s, 1H), 6.88 (s, 1H), 6.05 (s,1H), 4.15 (s, 2H), 3.98 (s, 2H), 3.51 (m, J=6.43, 2H), 1.02 (d, J=6.43,6H); ¹³C NMR (125 MHz, DMSO-d₆): δ 144.9 (C), 144.3 (C), 142.5 (C),142.4 (C), 130.5 (C), 129.3 (C), 127.5 (C), 115.4 (CH), 114.5 (C), 114.3(C), 113.9 (CH), 112.9 (C), 79.1 (CH), 67.6 (CH₂), 38.3 (CH₂), 21.7(2×CH₃); EIMS m/z 544/542/540/538[M]⁺ (1/3/3/1), 484/482/480/478(2/7/7/2), 467/465/463/461 (2/6/6/2), 403/401/399 (5/10/5), 322/320(10/9), 82/80 (98/100), 59 (30); HRMS: [M-H]^(− calcd for C) ₁₇H₁₆O₅⁷⁹Br₃: 536.8548; found: 536.8525.

Synthesis and characterization of

3,4-dibromo-5-(2-bromo-6-(butoxymethyl)-3,4-dihydroxybenzyl)benzene-1,2-diol(4)

Under 0° C. condition, to a solution of(3-bromo-2-(2′,3′-dibromo-4′,5′-dimethoxybenzyl)-4,5-dimethoxyphenyl)-methanolin CH₂Cl₂ was added dropwise BBr₃ (1 mol·L⁻¹ in CH₂Cl₂, mass ratio,BBr₃:compound 8=6:1˜8:1). The reaction mixture stirred over night atroom temperature. Then the mixture was poured into ice-cold water andextracted with EtOAc for three times. The organic lay was collected, andconcentrated in vacuo. The residue was dissolved in n-butyl alcohol andadded 1˜5 mL 85% H₃PO₄. After refluxing for 10-12 hours, the solvent wasremoved in vacuo. The residue was purified by column chromatographyeluted with petroleum ether and ethyl acetate (8:1) to produce yellowsolid. Spectrum analysis verified the compound is3,4-dibromo-5-(2-bromo-6-(butoxymethyl)-3,4-dihydroxybenzyl)benzene-1,2-diol.

The physical and chemical properties: ¹H NMR (500 MHz, DMSO-d₆): δ 9.75(s, 1H), 9.69 (s, 1H), 9.27 (s, 1H), 9.15 (s, 1H), 6.87 (s, 1H), 6.04(s, 1H), 4.16 (s, 2H), 3.98 (s, 2H), 3.29 (t, J=6.44, 2H), 1.36 (m, 2H),1.22 (m, 2H), 0.80 (t, J=7.35, 3H); ¹³C NMR (125 MHz, DMSO-d₆): δ 144.9(C), 144.2 (C), 142.5 (2×C), 130.5 (C), 129.0 (C), 127.5 (C), 115.4(CH), 114.6 (C), 114.3 (CH), 113.9 (C), 112.9 (C), 70.4 (CH₂), 69.2(CH₂), 38.3 (CH₂), 31.1 (CH₂), 18.7 (CH₂), 13.6 (CH₃); EIMS m/z484/482/480/478 (2/7/7/2), 467/465/463/461 (2/6/6/2), 403/401/399(5/10/5), 322/320 (13/12), 82/80 (18/18), 59 (100); HRMS: [M-H]⁻ calcdfor C₁₈H₁₈O₅ ⁷⁹Br₃: 550.8704; found: 550.8688.

Synthesis and characterization of

3,4-dibromo-5-bromo-3,4-dihydroxy-6-(isobutoxymethyl)benzyl)benzene-1,2-diol(5)

Under 0° C. condition, to a solution of(3-bromo-2-(2′,3′-dibromo-4′,5′-dimethoxybenzyl)-4,5-dimethoxyphenyl)-methanolin CH₂Cl₂ was added dropwise BBr₃ (1 mol·L⁻¹ in CH₂Cl₂, mass ratio,BBr₃:compound 8=6:1˜8:1). The reaction mixture stirred over night atroom temperature. Then the mixture was poured into ice-cold water andextracted with EtOAc for three times. The organic lay was collected, andconcentrated in vacuo. The residue was dissolved in isobutanol and added1˜5 mL 85% H₃PO₄. After refluxing for 10-12 hours, the solvent wasremoved in vacuo. The residue was purified by column chromatographyeluted with petroleum ether and ethyl acetate (8:1) to produce yellowsolid. Spectrum analysis verified the compound is3,4-dibromo-5-(2-bromo-3,4-dihydroxy-6-(isobutoxymethyl)benzyl)benzene-1,2-diol.

The physical and chemical properties: ¹H NMR (500 MHz, DMSO-d₆): δ 9.75(s, 1H), 9.69 (s, 1H), 9.27 (s, 1H), 9.15 (s, 1H), 6.88 (s, 1H), 6.04(s, 1H), 4.16 (s, 2H), 3.98 (s, 2H), 3.08 (d, J=6.48, 2H), 1.68 (m, 1H),0.78 (d, J=6.68, 6H); ¹³C NMR (125 MHz, DMSO-d₆): δ 144.9 (C), 144.2(C), 142.5 (2×C), 130.5 (C), 129.0 (C), 127.5 (C), 115.4 (CH), 114.6(C), 114.3 (CH), 113.9 (C), 113.0 (C), 76.4 (CH₂), 70.6 (CH₂), 38.3(CH₂), 27.8 (CH), 19.1 (2×CH₃); EIMS m/z 558/556/554/552 [M]⁺ (1/3/3/1),484/482/480/478 (5/15/14/5), 467/465/463/461 (3/9/10/3), 404/402/400(5/10/7), 403/401/399 (10/21/10), 322/320 (27/25), 82/80 (99/100), 57(40); HRMS: [M-H]⁻ calcd for C₁₈H₁₈O₅ ⁷⁹Br₃: 550.8704; found: 550.8688.

Scheme 3 shows the preparation of

2,3-dibromo-1-(2′-bromo-6′-(2″-bromo-4″,5″-dimethoxybenzyl)-3′,4′-dimethoxybenzyl)-4,5-dimethoxybenzene(6).

Schceme 3 (1) AlCl₃, CH₂Cl₂, room temperature; (m) Bromine, CH₂Cl_(2.)

Synthesis and characterization of

2,3-dibromo-1-(2′-bromo-6′-(3″,4″-dimethoxybenzyl)-3′,4′-dimethoxybenzyl)-4,5-dimethoxybenzene(17)

Under ice bath condition, to a solution of veratrole (mass concentration5˜10%) and

(3-bromo-2-(2′,3′-dibromo-4′,5′-dimethoxybenzyl)-4,5-dimethoxyphenyl)-methanol(mass concentration 5˜10%) in CH₂Cl₂ was added AlCl₃ (mole ratio,AlCl₃:veratrole:(3-bromo-2-(2′,3′-dibromo-4′,5′-dimethoxybenzyl)-4,5-imethoxyphenyl)-methanol=1.2:1:1)with stirring. TLC was used to monitor the reaction. The mixture waspoured into ice-water. The organic phase was washed with 3% HCl forthree times, then dried over anhydrous MgSO₄ and concentrated in vacuo.The residue was recrystallized from MeOH to give white solid. Spectrumanalysis verified the compound is2,3-dibromo-1-(2′-bromo-6′-(3″,4″-dimethoxybenzyl)-3′,4′-dimethoxybenzyl)-4,5-dimethoxybenzene.

The physical and chemical properties: m.p. 138-139° C. ¹H-NMR (500 MHz,DMSO-d₆)δ: 6.78 (s, 1H), 6.66 (d, J=8.06 Hz, 1H), 6.50 (d, J=8.06 Hz,1H), 6.49 (s, 1H), 5.99 (s, 1H), 4.18 (s, 2H), 3.88 (s, 3H), 3.87 (s,3H), 3.79 (s, 3H), 3.78 (s, 3 H), 3.75 (s, 3H), 3.51 (s, 3H); ¹³C-NMR(125 MHz, DMSO-d₆)δ: 152.1, 148.8, 147.4, 145.9, 145.3, 137.3, 135.7,131.9, 129.7, 122.8, 121.3, 120.5, 117.2, 114.1, 112.1, 112.0, 111.2,60.4, 60.3, 56.0, 55.9, 55.8, 55.7, 40.3, 39.8.

Synthesis and characterization of

2,3-dibromo-1-(2′-bromo-6′-(2″-bromo-4″,5″-dimethoxybenzyl)-3′,4′-dimethoxybenzyl)-4,5-dimethoxybenzene(6)

At room temperature, to a solution of2,3-dibromo-1-(2′-bromo-6′-(3″,4″-dimethoxybenzyl)-3′,4′-dimethoxybenzyl)-4,5-dimethoxybenzenein CH₂Cl₂ was added dropwise bromine (mole ratio,bromine:2,3-dibromo-1-(2′-bromo-6′-(3″,4″-dimethoxybenzyl)-3′,4′-dimethoxybenzyl)-4,5-dimethoxybenzene=2:1).TLC was used to monitor the reaction. The solvent was evaporated and theresidue was redissolved in CHCl₃. The organic phase was washed with 5%Na₂SO₃ for two times, and concentrated in vacuo. The residue wasrecrystallized in methanol to give white solid. Spectrum analysisverified the compound is2,3-dibromo-1-(2′-bromo-6′-(2″-bromo-4″,5″-dimethoxybenzyl)-3′,4′-dimethoxybenzyl)-4,5-dimethoxybenzene.

The physical and chemical properties: m.p. 151-152° C. ¹H-NMR (500 MHz,DMSO-d₆)δ: 6.97 (s, 1H), 6.56 (s, 1H), 6.41 (s, 1H), 6.16 (s, 1H), 4.23(s, 1H), 3.86 (s, 3H), 3.83 (s, 3H), 3.80 (s, 3H), 3.76 (s, 3H), 3.70(s, 3H), 3.57 (s, 3H); ¹³C-NMR (125 MHz, DMSO-d₆)δ: 152.2, 152.1, 148.5,146.0, 146.0, 145.3, 135.9, 135.5, 130.5, 129.6, 122.6, 121.6, 117.6,115.7, 114.9, 113.7, 113.5, 112.0, 60.5, 60.4, 56.1, 56.1, 56.0×2, 40.3,39.6.

All of the PTP1B inhibitors are compounds with PTP1B inhibitoryactivity. The compounds has been implicated in the negative regulationof insulin signal transduction pathways, enhanced insulin sensitivityand modulated blood glucose, and could be used for treating type 2diabetes mellitus.

PTP1B Inhibition Assay

Construct human recombinant PTP1B engineering bacteria hGST-PTP1B-BL21via molecular biology methods, and purify it through GST-tagged affinitychromatography. The principle is that the product pNP, which isenzymolysis of pNPP by PTP1B, absorbs at 405 nm. The activity of PTP1Binhibition can be measured by calculating the quantity of pNP.

The advantages of this invention are as follows:

The target compounds are with potent PTP1B inhibitory activities, andare promising for treatment of insulin resistance T2DM. The inventionhas implemented total synthesis of target compounds. The startingmaterials are cheap and commercial available, the procedures are simpleand yields are acceptable. So the preparation of these compounds havegood scale-up perspective.

EXAMPLES Example 1 Synthesis and Characterizaion of(2′-bromo-6′-(dibromomethyl)-3′,4′-dimethoxyphenyl)-(2,3-dibromo-4,5-dimethoxyphenyl)-methanone(1)

Synthesis and Characterizaion of 5-bromo-vanilline (8)

To a solution of vanillin (7.6 g, 50 mmol) in MeOH (60 mL) was addeddropwise Br₂ (2.8 mL, 50 mmol) over a 2 h period at 0° C. The mixturewas warm to room temperature for another 1 h. Then cooling to 0° C.,water (25 mL) was poured over a 20 min period and resulted in theprecipitation of white solid. The mixture was stirred for further 15min. The precipitate was filtered, washed with ice water and dried togive 10.7 g of white solid. Spectrum analysis verified the compound is5-Br-vanillin.

The physical and chemical properties: m.p. 160-162° C. ¹H-NMR (500 MHz,CDCl₃) δ: 9.78 (s, 1H), 7.64 (d, J=1.65 Hz, 1H), 7.36 (d, J=1.65 Hz,2H), 3.98 (s, 3H); ¹³C-NMR (125 MHz, CDCl₃) δ: 189.5 (CHO), 148.9 (C),147.7 (C), 130.1, 130.0 (C), 108.2 (C), 108.1 (CH), 56.6 (CH₃).

Synthesis and Characterization of 5-bromo-veratraldehyde (9)

At room temperature, to a suspension of 5-Br-vanillin (4.26 g, 18 mmol)and K₂CO₃ (3.84 g, 24 mmol) in DMF (40 mL) was added CH₃I (1.7 mL, 33mmol) dropwise. After stirring for 24 h, 20% brine (100 mL) was added toquench the reaction. The mixture was extracted with tert-butyl methylether (3×100 mL). The organic layer was collected, washed with 20%brine, dried over anhydrous MgSO₄ and concentrated in vacuo to give 4.2g white solid. Spectrum analysis verified the compound is5-bromo-veratraldehyde.

The physical and chemical properties: m.p. 60-62° C. ¹H-NMR (500 MHz,CDCl₃) δ: 9.84 (s, 1H), 7.64 (s, 1H), 7.38 (s, 1H), 3.94 (s, 3H), 3.93(s, 3H); ¹³C-NMR (125 MHz, CDCl₃) δ: 189.7 (CHO), 154.2 (C), 151.8 (C),133.1 (C), 128.7 (CH), 117.9 (CH), 110.2 (C), 60.8 (CH₃), 56.2 (CH₃).

Synthesis and Characterization of 5-bromo-3,4-dimethoxy-methylbenzene(10)

At room temperature, to a solution of 5-bromo-veratraldehyde (29.4 g,120 mmol) in diglycol (200 mL) was added 80% hydrazine hydrate (13 mL).TLC was used to monitor the reation. Then 24 g KOH was added and themixture was heated to 120° C. for 2 h. After cooling, the resultingmixture was poured into water (200 mL), and extracted with 200 mL CH₂Cl₂for three times. The organic lay was collected, washed with 1 mol/L HCl(3×200 mL), dried over anhydrous Na₂SO₄ and concentrated in vacuo togive 24 g colorless oil. Spectrum analysis verified the compound is5-bromo-3,4-dimethoxy-methylbenzene

The physical and chemical properties: ¹H-NMR (500 MHz, CDCl₃) δ: 6.94(s, 1H), 6.65 (s, 1H), 3.84 (s, 3H), 3.82 (s, 3H), 2.28 (s, 3H); ¹³C-NMR(125 MHz, CDCl₃) δ: 153.3 (C), 144.1 (C), 135.1 (C), 124.8 (CH), 117.1(C), 112.5 (CH), 60.4 (CH₃), 55.9 (CH₃), 21.0 (CH₃).

Synthesis and Characterization of 5,6-dibromo-veratraldehyde (11)

At room temperature, to a solution of 5-bromo-veratraldehyde (31 g, 126mmol) in AcOH (220 mL) was added dropwise Br₂ (12.6 mL, 244 mmol) andiron powder (100 mg). The mixture was heated at 60° C. and stirred for 5h. After cooling to room temperature, the iron powder was filtered andthe filtrate was removed in vacuo. The residue was redissolved in CHCl₃(200 mL), and washed with 5% Na₂SO₃ (2×200 mL). The organic lay wascollected, and concentrated in vacuo. The residue was recrystallized inacetone to give 27 g white needle crystal. Spectrum analysis verifiedthe compound is 5,6-dibromo-veratraldehyde.

m.p. 128-130° C. ¹H-NMR (500 MHz, CDCl₃) δ: 10.27 (s, 1H), 7.48 (s, 1H),3.94 (s, 3H), 3.92 (s, 3H); ¹³C-NMR (125 MHz, CDCl₃) δ: 191.5 (CHO),152.8 (C), 131.0 (C), 122.8 (C), 121.9 (C), 111.7 (CH), 60.8 (CH₃), 56.3(CH₃).

Synthesis and Characterization of 5,6-dibromo-veratric acid (12)

5,6-dibromo-veratraldehyde (38 g, 117 mmol) and NaHCO₃(5.7 g, 80 mmol)and water (300 mL) were placed in a 500 mL three-necked round bottomflask. The suspension was heated to 90° C. and added KMnO₄ (19.0 g, 100mmol) in three portions. TLC was used to monitor the reaction and theMnO₂ was filtered. The filtrate was acidified. The white precipitate wasfiltered and washed with water to give 36.3 g white solid. Spectrumanalysis verified the compound is 5,6-dibromo-veratric acid.

The physical and chemical properties: m.p. 180-181° C.; ¹H NMR (500 MHz,CD₃OCD₃): δ 7.39 (s, 1H, H-2), 3.90 (s, 3H, H-8), 3.87 (s, 3H, H-9); ¹³CNMR (125 MHz, CD₃OCD₃): δ 169.2 (C-7), 153.6 (C-4), 150.9 (C-3), 132.8(C-1), 127.5 (C-6), 123.8 (C-5), 114.5 (C-2), 60.9 (C-8), 56.9 (C-9).

Synthesis and characterization of

(2-bromo-3,4-dimethoxy-6-methylphenyl)-(2,3-dibromo-4,5-dimethoxyphenyl)-methanone(13)

Under ice bath condition, to a solution of 5,6-dibromo-veratraldehyde(2.4 g, 7 mmol) in TFAA (10 mL) was added 85% H₃PO₄ (0.5 mL) and5-bromo-3,4-dimethoxy-methylbenzene (1.71 g, 7.5 mmol). The mixture washeated to 60° C. TLC was used to monitor the reaction. Then the mixturewas poured into crushed ice and extracted with CHCl₃. The organic layerwas collected dried over anhydrous MgSO₄ and concentrated in vacuo. Theresidue was recrystallized in EtOH to give 3.5 g white crystal. Spectrumanalysis verified the compound is(2-bromo-3,4-dimethoxy-6-methylphenyl)-(2,3-dibromo-4,5-dimethoxyphenyl)-methanone.

The physical and chemical properties: m.p. 86-88° C.; ¹H NMR (500 MHz,CDCl₃): δ7.16 (s, 1H, H-6), 6.74 (s, 1H, H-5′), 3.90 (s, 3H, H-9), 3.90(s, 3H, H-11), 3.81 (s, 3H, H-10), 3.79 (s, 3H, H-12), 2.22 (s, 3H,H-8); ¹³C NMR (125 MHz, CDCl₃): δ 194.2 (C-7), 154.0 (C-4), 152.0(C-4′), 150.8 (C-5), 144.6 (C-3′), 135.7 (C-1), 133.7 (C-1′), 133.0(C-6′), 124.3 (C-2), 116.3 (C-2′), 115.5 (C-3), 115.1 (C-6), 113.8(C-5′), 60.6 (C-9,11), 56.3 (C-10), 56.0 (C-12), 20.2 (C-8).

Synthesis and characterization of

(2-bromo-6-(dibromomethyl)-3,4-dimethoxyphenyl)-(2,3-dibromo-4,5-dimethoxyphenyl)-methanone(1)(2-bromo-3,4-climethoxy-6-methylphenyl)-(2,3-dibmmo-4,5-dimethoxyphenyl)-methanone(4.29 g, 7.8 mmol), AIBN (43 mg) and NBS (3.45 g, 19,4 mmol) weredissolved in CCl₄ (50 mL). The mixture was heated to reflux and TLC wasused to monitor the reaction. Then the precipitate was filtered off andthe solvent was removed in vacuo to produce a brownish residue. Theresidue was purified by chromatography eluted with petroleum ether andethyl acetate (20:1) to give 1.95 g white solid. Spectrum analysisverified the compound is(2-bromo-6-(dibromomethyl)-3,4-dimethoxyphenyl)-(2,3-dibromo-4,5-dimethoxyphenyl)-methanone

The physical and chemical properties: m.p. 166-169° C.; ¹H NMR (500 MHz,CDCl₃): δ 7.58 (s, 1H), 7.07 (s, 1H), 6.66 (s, 1H), 4.03 (s, 3H), 3.93(s, 3H), 3.87 (s, 3H), 3.78 (s, 3H); ¹³C NMR (125 MHz, CDCl₃): δ 192.8(CO), 155.1, 152.0, 151.2, 147.6, 137.4, 135.2, 129.2, 124.7, 116.8,115.1, 114.4, 113.5, 60.8 (2×CH₃), 56.4 (2×CH₃), 36.7 (CHBr₂); HRMS:[M+H]⁺ calcd for C₁₈H₁₆O₅Br₅: 706.6915, found: 706.6882.

Example 2 Synthesis and Characterization of

3,4-dibromo-5-[2′-bromo-3′,4′-dihydroxy-6′-(propoxymethyl)-benzyl]-benzene-1,2-diol (2),3,4-dibromo-5-[2′-bromo-3′,4′-dihydroxy-6′-(isopropoxymethyl)-benzyl]-benzene-1,2-diol(3),3,4-dibromo-5-[2′-bromo-6′-(butoxymethyl)-3′,4′-dihydroxy-benzyl]-benzene-1,2-diol(4),3,4-dibromo-5-[2′-bromo-3′,4′-dihydroxy-6′-(isobutoxymethyl)-benzyl]-benzene-1,2-diol(5)

Synthesis and Characterization of5,6-dibromo-3,4-dimethoxy-phenyl-methanol (14)

Under ice bath condition, to a stirred solution of5,6-dibromo-veratraldehyde (72 g, 222 mmol) in MeOH (400 mL) was addedNaBH₄ (2.2 g, 5.5 mmol). TLC was used to monitor the reaction. Then 10%HCl was added to adjust the reaction to weak acidity. MeOH wasevaporated and extracted with CH₂Cl₂. The organic lay was collected,dried over anhydrous MgSO₄ and concentrated in vacuo to give 66 g whitesolid. Spectrum analysis verified the compound is5,6-dibromo-3,4-dimethoxy-phenyl-methanol.

The physical and chemical properties: m.p. 91-93° C. ¹H-NMR (500 MHz,CDCl₃) δ: 7.01 (s, 1H), 4.71 (s, 2H), 3.88 (s, 3H), 3.84 (s, 3H);¹³C-NMR (125 MHz, CDCl₃) δ: 152.7 (C), 146.8 (C), 137.3 (C), 121.7 (C),114.9 (C), 111.5 (CH), 65.9 (CH₂), 60.5 (CH₃), 56.2 (CH₃).

Synthesis and characterization of2,3-dibromo-1-(2′-bromo-3′,4′-dimethoxy-6′-methylbenzyl)-4,5-dimethoxybenzene (15)

Under ice bath condition, to a stirred solution of5-bromo-3,4-dimethoxy-methylbenzene (23.1 g, 100 mmol) and5,6-dibromo-3,4-dimethoxy-phenyl-methanol (32.6 g, 100 mmol) in CH₂Cl₂(300 mL) was added AlCl₃ (13.4 g, 100 mmol). TLC was used to monitor thereaction. Then the mixture was poured into ice water (100 mL). Theorganic layer was collected and washed with 3% HCl (3×200 mL), driedover anhydrous MgSO₄ and concentrated in vacuo. The residue wasrecrystallized from MeOH to give 48 g white solid. Spectrum analysisverified the compound is2,3-dibromo-1-(2′-bromo-3′,4′-dimethoxy-6′-methylbenzyl)-4,5-dimethoxybenzene.

The physical and chemical properties: m.p. 114-117° C. ¹H-NMR (500 MHz,CDCl₃) δ: 6.76 (s, 1H), 6.15 (s, 1H), 4.19 (s, 2H), 3.89 (s, 3H), 3.84(s, 3H), 3.81 (s, 3H), 3.56 (s, 3H), 2.17 (s, 3H); ¹³C-NMR (125 MHz,CDCl₃) δ: 152.5 (C), 152.0 (C), 146.1 (C), 144.9 (C), 135.8 (C), 134.3(C), 129.6 (C), 122.1 (C), 121.7 (C), 117.6 (C), 113.8 (CH), 111.7 (CH),60.4 (2×CH₃), 56.1 (CH₃), 56.0 (CH₃), 40.5 (CH₂), 20.6 (CH₃).

Synthesis and characterization of

(3-bromo-2-(2′,3′-dibromo-4′,5′-dimethoxybenzyl)-4,5-dimethoxyphenyl)-methanol(16)

Under hυ condition, to a solution of AIBN (350 mg) and2,3-dibromo-1-(2′-bromo-3′,4′-dimethoxy-6′-methylbenzyl)-4,5-dimethoxybenzene (35 g, 65 mmol) in CCl₄ (400 mL) was added NBS (12.7 g, 71mmol). TLC was used to monitor the reaction. The precipitate wasfiltered off and the solvent was removed in vacuo to produce a brownishresidue. The residue was purified by chromatography eluted withpetroleum ether and ethyl acetate (8:1) to give benzyl bromide as whitesolid. The white solid and K₂CO₃ (mass ratio 2:1) were dissolved inmixture of dixoane and H₂O (60 mL, volume ratio 1:1) and the reactionwas heated to 90° C. TLC was used to monitor the reaction. The mixturewas extracted with CHCl₃ (100 mL) and H₂O (100 mL). The organic lay wascollected and concentrated in vacuo to give 12.5 g white solid. Spectrumanalysis verified the compound is(3-bromo-2-(2′,3′-dibromo-4′,5′-dimethoxybenzyl)-4,5-dimethoxyphenyl)-methanol.

The physical and chemical properties: m.p. 164-166° C. ¹H-NMR (500 MHz,CDCl₃) δ: 7.09 (s, 1H), 6.14 (s, 1H), 4.52 (s, 2H), 4.22 (s, 2H), 3.91(s, 3H), 3.86 (s, 3H), 3.79 (s, 3H), 3.55 (s, 3H); ¹³C-NMR (125 MHz,CDCl₃) δ: 152.4 (2×C), 146.1 (C), 145.9 (C), 136.6 (C), 135.8 (C), 128.7(C), 122.5 (C), 121.7 (C), 117.4 (C), 111.8 (CH), 111.4 (CH), 63.0(CH₂), 60.4 (2×CH₃), 56.0 (2×CH₃), 39.2 (CH₂).

Synthesis and characterization of

3,4-dibromo-5-(2-bromo-3,4-dihydroxy-6-(propoxymethyl)benzyl)benzene-1,2-diol(2)

(3-bromo-2-(2′,3′-dibromo-4′,5′-dimethoxybenzyl)-4,5-dimethoxyphenyl)-methanol(0.90 g, 1 mmol) was dissolved in 20 mL CH₂Cl₂, then BBr₃ (1 mol·L⁻¹ inCH₂Cl₂, 16 mL) was added dropwise while stirring at 0° C. The reactionmixture stirred over night at room temperature. Then the solution waspoured into ice water (50 mL) and extracted with EtOAc (3×50 mL). Theorganic lay was collected, and concentrated in vacuo. The residue wasdissolved in n-propanol (15 mL) and H₃PO₄ (1 mL). After refluxing for 12hours, the solvent was removed in vacuo. The residue was purified bycolumn chromatography eluted with petroleum etherand EtOAc (1:1) toproduce 0.5 g yellow solid. Spectrum analysis verified the compound is3,4-dibromo-5-(2-bromo-3,4-dihydroxy-6-(propoxymethyl)benzyl)benzene-1,2-diol

The physical and chemical properties: ¹H NMR (500 MHz, DMSO-d₆): δ 9.75(s, 1H), 9.69 (s, 1H), 9.27 (s, 1H), 9.14 (s, 1H), 6.88 (s, 1H), 6.05(s, 1H), 4.17 (s, 2H), 3.99 (s, 2H), 3.26 (t, J=6.52, 2H), 1.14 (m, J=,2H), 0.79 (t, J=7.36, 3H); 13C NMR (125 MHz, DMSO-d6): δ 144.9 (C),144.3 (C), 142.5 (2×C), 130.5 (C), 129.0 (C), 127.5 (C), 115.4, 114.6(C), 114.3, 113.9 (C), 112.9 (C), 71.2 (CH₂), 70.3 (CH₂), 38.3 (CH₂),22.2 (CH₂), 10.4 (CH₃); EIMS m/z 544/542/540/538[M]⁺ (1/3/3/1),484/482/480/478 (2/7/7/2), 467/465/463/461 (2/6/6/2), 403/401/399(7/15/7), 322/320 (19/18), 82/80 (42/43), 59 (100); HRMS: [M-H]⁻ calcdfor C₁₇H₁₆O₅ ⁷⁹Br₃: 536.8548; found: 536.8570.

Synthesis and characterization of

3,4-dibromo-5-(2-bromo-3,4-dihydroxy-6-(isopropoxymethyl)benzyl)benzene-1,2-diol(3)(3-bromo-2-(2′,3′-dibromo-4′,5′-dimethoxybenzyl)-4,5-dimethoxyphenyl)-methanol(0.90 g, 1 mmol) was dissolved in 20 mL CH₂Cl₂, then BBr₃ (1 mol·L⁻¹ inCH₂Cl₂, 16 mL) was added dropwise while stirring at 0° C. The reactionmixture stirred over night at room temperature. Then the solution waspoured into ice water (50 mL) and extracted with EtOAc (3×50 mL). Theorganic lay was collected, and concentrated in vacuo. The residue wasdissolved in iso-propanol (15 mL) and H₃PO₄ (1 mL). After refluxing for12 hours, the solvent was removed in vacuo. The residue was purified bycolumn chromatography eluted with petroleum etherand EtOAc (1:1) toproduce 0.5 g yellow solid. Spectrum analysis verified the compound is3,4-dibromo-5-(2-bromo-3,4-dihydroxy-6-(isopropoxymethyl)benzyl)benzene-1,2-diol

The physical and chemical properties: ¹H NMR (500 MHz, DMSO-d₆): δ 9.72(s, 1H), 9.69 (s, 1H), 9.26 (s, 1H), 9.11 (s, 1H), 6.88 (s, 1H), 6.05(s, 1H), 4.15 (s, 2H), 3.98 (s, 2H), 3.51 (m, J=6.43, 2H), 1.02 (d,J=6.43, 6H); ¹³C NMR (125 MHz, DMSO-d₆): δ 144.9 (C), 144.3 (C), 142.5(C), 142.4 (C), 130.5 (C), 129.3 (C), 127.5 (C), 115.4 (CH), 114.5 (C),114.3 (C), 113.9 (CH), 112.9 (C), 79.1 (CH), 67.6 (CH₂), 38.3 (CH₂),21.7 (2×CH₃); EIMS m/z 544/542/540/538[M]⁺ (1/3/3/1), 484/482/480/478(2/7/7/2), 467/465/463/461 (2/6/6/2), 403/401/399 (5/10/5), 322/320(10/9), 82/80 (98/100), 59 (30); HRMS: [M-H]⁻ calcd for C₁₇H₁₆O₅ ⁷⁹Br₃:536.8548; found: 536.8525.

Synthesis and characterization of

3,4-dibromo-5-(2-bromo-6-(butoxymethyl)-3,4-dihydroxybenzyl)benzene-1,2-diol(4)

(3-bromo-2-(2′,3′-dibromo-4′,5′-dimethoxybenzyl)-4,5-dimethoxyphenyl)-methanol(0.90 g, 1 mmol) was dissolved in 20 mL CH₂Cl₂, then BBr₃ (1 mol·L⁻¹ inCH₂Cl₂, 16 mL) was added dropwise while stirring at 0° C. The reactionmixture stirred over night at room temperature. Then the solution waspoured into ice water (50 mL) and extracted with EtOAc (3×50 mL). Theorganic lay was collected, and concentrated in vacuo. The residue wasdissolved in n-butyl alcohol (15 mL) and H₃PO₄ (1 mL). After refluxingfor 12 hours, the solvent was removed in vacuo. The residue was purifiedby column chromatography eluted with petroleum etherand EtOAc (1:1) toproduce 0.4 g yellow solid. Spectrum analysis verified the compound is3,4-dibromo-5-(2-bromo-6-(butoxymethyl)-3,4-dihydroxybenzyl)benzene-1,2-diol.

The physical and chemical properties: ¹H NMR (500 MHz, DMSO-d₆): δ 9.75(s, 1H), 9.69 (s, 1H), 9.27 (s, 1H), 9.15 (s, 1H), 6.87 (s, 1H), 6.04(s, 1H), 4.16 (s, 2H), 3.98 (s, 2H), 3.29 (t, J=6.44, 2H), 1.36 (m, 2H),1.22 (m, 2H), 0.80 (t, J=7.35, 3H); ¹³C NMR (125 MHz, DMSO-d₆): δ 144.9(C), 144.2 (C), 142.5 (2×C), 130.5 (C), 129.0 (C), 127.5 (C), 115.4(CH), 114.6 (C), 114.3 (CH), 113.9 (C), 112.9 (C), 70.4 (CH₂), 69.2(CH₂), 38.3 (CH₂), 31.1 (CH₂), 18.7 (CH₂), 13.6 (CH₃); EIMS m/z484/482/480/478 (2/7/7/2), 467/465/463/461 (2/6/6/2), 403/401/399(5/10/5), 322/320 (13/12), 82/80 (18/18), 59 (100); HRMS: [M-H]⁻¹ calcdfor C₁₈H₁₈O₅ ⁷⁹Br₃: 550.8704; found: 550.8688.

Synthesis and characterization of

3,4-dibromo-5-(2-bromo-3,4-dihydroxy-6-(isobutoxymethyl)benzyl)benzene-1,2-diol(5)

(3-bromo-2-(2′,3′-dibromo-4′,5′-dimethoxybenzyl)-4,5-dimethoxyphenyl)-methanol(0.90 g, 1 mmol) was dissolved in 20 mL CH₂Cl₂, then BBr₃ (1 mol·L⁻¹ inCH₂Cl₂, 16 mL) was added dropwise while stirring at 0° C. The reactionmixture stirred over night at room temperature. Then the solution waspoured into ice water (50 mL) and extracted with EtOAc (3×50 mL). Theorganic lay was collected, and concentrated in vacuo. The residue wasdissolved in iso-butanol (15 mL) and H₃PO₄ (1 mL). After refluxing for12 hours, the solvent was removed in vacuo. The residue was purified bycolumn chromatography eluted with petroleum etherand EtOAc (1:1) toproduce 0.35 g yellow solid. Spectrum analysis verified the compound is3,4-dibromo-5-(2-bromo-3,4-dihydroxy-6-(isobutoxymethyl)benzypbenzene-1,2-diol.

The physical and chemical properties: ¹H NMR (500 MHz, DMSO-d₆): δ 9.75(s, 1H), 9.69 (s, 1H), 9.27 (s, 1H), 9.15 (s, 1H), 6.88 (s, 1H), 6.04(s, 1H), 4.16 (s, 2H), 3.98 (s, 2H), 3.08 (d, J=6.48, 2H), 1.68 (m, 1H),0.78 (d, J=6.68, 6H); ¹³C NMR (125 MHz, DMSO-d₆):δ 144.9 (C), 144.2 (C),142.5 (2×C), 130.5 (C), 129.0 (C), 127.5 (C), 115.4 (CH), 114.6 (C),114.3 (CH), 113.9 (C), 113.0 (C), 76.4 (CH₂), 70.6 (CH₂), 38.3 (CH₂),27.8 (CH), 19.1 (2×CH₃); EIMS m/z 558/556/554/552 [M]⁺ (1/3/3/1),484/482/480/478 (5/15/14/5), 467/465/463/461 (3/9/10/3), 404/402/400(5/10/7), 403/401/399 (10/21/10), 322/320 (27/25), 82/80 (99/100), 57(40); HRMS: [M-H]⁻¹ calcd for C₁₈H₁₈O₅ ⁷⁹Br₃: 550.8704; found: 550.8680.

Example 3 Synthesis and Characterization of2,3-dibromo-1-[2′-bromo-6′-(2″-bromo-4″,5″-dimethoxybenzyl)-3′,4′-dimethoxybenzyl]-4,5-dimethoxybenzene (6).

Synthesis and characterization of

2,3-dibromo-1-(2′-bromo-6″-(3″,4″-dimethoxybenzyl)-3′,4′-dimethoxybenzyl)-4,5-dimethoxybenzene(17)

Under ice bath condition, to a solution of veratrole (0.69 g, 5 mmol)and(3-bromo-2-(2′,3′-dibromo-4′,5′-dimethoxybenzyl)-4,5-dimethoxyphenyl)-methanol(2.78 g, 5 mmol) in CH₂Cl₂ was added AlCl₃ (0.8 g, 7 mmol). TLC was usedto monitor the reaction. The mixture was poured into ice-water. Theorganic phase was washed with 3% HCl for three times, then dried overanhydrous MgSO₄ and concentrated in vacuo. The residue wasrecrystallized from MeOH to give 2.8 g white solid. Spectrum analysisverified the compound is2,3-dibromo-1-(2′-bromo-6′-(3″,4″-dimethoxybenzyl)-3′,4′-dimethoxybenzyl)-4,5-dimethoxybenzene.

The physical and chemical properties: m.p. 138-139° C. ¹H-NMR (500 MHz,DMSO-d₆)δ: 6.78(s, 1H), 6.66 (d, J=8.06 Hz, 1H), 6.50 (d, J=8.06 Hz,1H), 6.49 (s, 1H), 5.99 (s, 1H), 4.18 (s, 2H), 3.88 (s, 3H), 3.87 (s,3H), 3.79 (s, 3H), 3.78 (s, 3H), 3.75 (s, 3H), 3.51 (s, 3H); ¹³C-NMR(125 MHz, DMSO-d₆)δ: 152.1, 148.8, 147.4, 145.9, 145.3, 137.3, 135.7,131.9, 129.7, 122.8, 121.3, 120.5, 117.2, 114.1, 112.1, 112.0, 111.2,60.4, 60.3, 56.0, 55.9, 55.8, 55.7, 40.3, 39.8.

Synthesis and characterization of

2,3-dibromo-1-(2′-bromo-6′-(2″-bromo-4″,5″-dimethoxybenzyl)-3′,4′-dimethoxybenzyl)-4,5-dimethoxybenzene(6)

At room temperature, to a solution of

2,3-dibromo-1-(2′-bromo-6′-(3″,4″-dimethoxybenzyl)-3′,4′-dimethoxybenzyl)-4,5-dimethoxybenzene(1 g, 1.48 mmol) in CH₂C1₂ (20 mL) was added dropwise bromine (0.15 mL,2.96 mmol). The reaction lasted 1-2 h. TLC was used to monitor thereaction. The solvent was evaporated and the residue was redissolved inCHCl₃. The organic phase was washed with 5% Na₂SO₃ for two times, andconcentrated in vacuo. The residue was recrystallized in MeOH to give0.844 g white solid. Spectrum analysis verified the compound is2,3-dibromo-1-(2′-bromo-6′-(2″-bromo-4″,5″-dimethoxybenzyl)-3′,4′-dimethoxybenzyl)-4,5-dimethoxybenzene.

The physical and chemical properties: m.p. 151-152° C. ¹H-NMR (500 MHz,DMSO-d₆)δ: 6.97 (s, 1H), 6.56 (s, 1H), 6.41(s, 1H), 6.16 (s, 1H), 4.23(s, 1H), 3.86 (s, 3H), 3.83 (s, 3H), 3.80 (s, 3H), 3.76 (s, 3H), 3.70(s, 3H), 3.57 (s, 3H); ¹³C-NMR (125 MHz, DMSO-d₆)δ: 152.2, 152.1, 148.5,146.0, 146.0, 145.3, 135.9, 135.5, 130.5, 129.6, 122.6, 121.6, 117.6,115.7, 114.9, 113.7, 113.5, 112.0, 60.5, 60.4, 56.1, 56.1, 56.0×2, 40.3,39.6.

Example 4 PTP1B Inhibitory Assay

Compounds 1, 2, 3, 4, 5 and 6 were dissolved in DMSO. 2 μL of sampleswere placed into the system (50 mM Tris-HCl, pH 6.5, 2 mM pNPP, 2% DMSO,30 nM hGST-PTP1B). DMSO was distributed as negative control and Na₃VO₄was positive control. The reaction was at 30° C. and monitored at 405 nmfor 3 min Inhibitory rate was calculated according to the followingformula:

% inhibition=100%×[(V _(sample)-V _(DMSO))/(V _(DMSO)-V _(DMSO))]

The results are shown in Table 1.

TABLE 1 Inhibitory Ratio (%) of PTPIB Inhibition (%) IC₅₀ Compds 20μg/mL 5 μg/mL (μg/mL) 1 101.4 47.85 1.31 2 86.15 55.70 1.08 3 93.8968.24 0.34 4 64.56 27.17 ND 5 96.25 48.30 0.83 6 96.50 42.40 1.01

The results showed that all of the compounds exhibit potent PTP1Binhibition, and are promising for treatment of T2DM.

1. An agent of PTP1B inhibitor, which contains one or more of thefollowed six compounds as active components, and the structures of thesix compounds are as follows:

Their chemical names are:(2′-bromo-6′-(dibromomethyl)-3′,4′-dimethoxyphenyl)-(2,3-dibromo-4,5-dimethoxyphenyl)-methanone (1),3,4-dibromo-5-[2′-bromo-3′,4′-dihydroxy-6′-(propoxymethyl)-benzyl]-benzene-1,2-diol(2),3,4-dibromo-5-[2′-bromo-3′,4′-dihydroxy-6′-(isopropoxymethyl)-benzyl]-benzene-1,2-diol (3),3,4-dibromo-5-[2′-bromo-6′-(butoxymethyl)-3′,4′-dihydroxy-benzyl]-benzene-1,2-diol(4),3,4-dibromo-5-[2′-bromo-3′,4′-dihydroxy-6′-(isobutoxymethyl)-benzyl]-benzene-1,2-diol(5),2,3-dibromo-1-[2′-bromo-6′-(2″-bromo-4″,5″-dimethoxybenzyl)-3′,4′-dimethoxybenzyl]-4,5-dimethoxybenzene(6).
 2. Synthetic methods of PTP1B inhibitor according to claim 1,wherein the synthetic routes of the six compounds as follows: (1)Synthetic route of compound 1

Scheme 1 (a) molar ratio of bromine and compound 7 is 1:1, MeOH, icebath condition; (b) molar ratio of methyl iodide and compound 8 is1:1˜1:1.5, K₂CO₃, DMF as solvent, room temperature; (c) a solution ofcompound 9 with mass concentration 10˜15% in diglycol, massconcentration 80% hydrazine hydrate solution, KOH, 110˜120° C.; (d)molar ratio of bromine and compound 9 is 2:1˜3:1, acetic acid, 60˜70°C.; (e) KMnO₄, water, 90° C.; (f) Trifluoroacetic anhydride, H₃PO₄,0˜60° C.; (g) N-Bromosuccinimide, AIBN, CCl₄, hυ. (2) Synthetic route ofcompound 2, 3, 4 and 5

Scheme 2 (h) NaBH₄, MeOH, 0° C.; (i) AlCl₃, CH₂Cl₂, 0° C.; (j)N-Bromosuccinimide, CCl₄, hv; H₂O, dioxane, reflux; (k) BBr₃, CH₂Cl₂, 0°C.; H₃PO₄, corresponding alcohol, 70˜80° C. (3) Synthetic route ofcompound 6

Schceme 3 (1) AlCl₃, CH₂Cl₂, room temperature; (m) Bromine, CH₂Cl₂. 3.Synthetic routes according to claim 2, wherein said the procedures ofcompound 1 are as follows: (1) Under ice bath condition, bromine wasadded dropwise to a solution of vanilline in MeOH within 1-2 hours. Massratio of vanilline: MeOH was 1:6˜1:7 and molo ratio of bromine:vanillinewas 1:1. The mixture is warmed to room temperature and stirred forfurther 0.5-1 hour. The mixture was cooled to 0° C. and added ice waterwithin 20-30 min Volume ratio of H₂O: MeOH was 1:2˜1:3. Then precipitatewas separated out. The mixture was stirred for further 15-30 min. Theprecipitate was filtered and washed with ice water and dried to givewhite solid. Spectrum analysis verified the compound is 5-Br-vanillin.(2) At room temperature, to a suspension of 5-Br-vanillin and K₂CO₃ inDMF was added dropwise CH₃I. Mass-volume ratio of K₂CO₃:DMF was 1:8˜1:12and mole ratio of CH₃I:5-Br-vanillin was 1:1˜1:1.5. After stirring for24 h, brine of mass concentration 18-22% was added to quench thereaction. Then the mixture was extracted with tert-butyl methyl etherfor three times. The organic layer was collected, washed with brine ofmass concentration 3-10%, dried over anhydrous Na₂SO₄ and concentratedin vacuo to give white solid. Spectrum analysis verified the compound is5-bromo-veratraldehyde. (3) At room temperature, to a diglycol solutionof 5-bromo-veratraldehyde with mass concentration 10-15% was added massconcentration 80% hydrazine hydrate. Mole ratio of3-bromo-4,5-dimethoxybenzaldehyde:hydrazine hydrate was 1:1˜1:1.5. TLCwas used to monitor the reaction. Then KOH with mass concentration 8-12%was added. The mixture was heated to 110-120° C. and stirred for 2-3hours. After cooling, the resulting mixture was poured into water, andextracted with CH₂Cl₂ for three times. The organic lay was collected,washed with 1 mol/L HCl, dried over anhydrous MgSO₄ and concentrated invacuo to give colorless oil. Spectrum analysis verified the compound is5-bromo-3,4-dimethoxy-methylbenzene. (4) At room temperature, to a AcOHsolution of 3-bromo-4,5-dimethoxybenzaldehyde with mass concentration10-15% was added dropwise bromine and catalyst iron powder. Mole ratioof bromine: 3-bromo-4,5-dimethoxybenzaldehyde was 2:1˜3:1. The mixturewas heated to 60-70° C. and stirred for 4-6 hours. After cooling to roomtemperature, the iron powder was filtered and the filtrate was removedin vacuo. The residue was redissolved in CHCl₃, and washed with 5%Na₂SO₃ for two times. The organic lay was collected, and concentrated invacuo. The residue was recrystallized in acetone to give white needlecrystal. Spectrum analysis verified the compound is5,6-dibromo-veratraldehyde. (5) NaHCO₃, 5,6-dibromo-veratraldehyde andH₂O were successively placed in a three-necked round bottom flask. Thesuspension was heated to 90° C. and added KMnO₄ in three portions. Moleratio of KMnO₄: 2,3-dibromo-4,5-dimethoxybenzaldehyde was 1:1˜1:1.5. TLCwas used to monitor the reaction. The MnO₂ was filtered and the filtratewas acidified. The white precipitate was filtered and dried to givewhite solid. Spectrum analysis verified the compound is5,6-dibromo-veratric acid. (6) Under ice bath condition,5,6-dibromo-veratric acid was placed in a three-necked round bottomflask and dissolved in TFAA. To the stirred solution was added 85% H₃PO₄and 5-bromo-3,4-dimethoxy-methylbenzene. Mole ratio of5-bromo-3,4-dimethoxy-methylbenzene:5,6-dibromo-veratric acid was 1:1.The mixture was heated to 60° C. and TLC was used to monitor thereaction. The mixture was poured into crushed ice and extracted withCHCl₃ for three times. The organic layer was collected and concentratedin vacuo. The residue was recrystallized in EtOH to give white crystal.Spectrum analysis verified the compound is(2′-bromo-3′,4′-dimethoxy-6′-methylphenyl)-(2,3-dibromo-4,5-dimethoxyphenyl)-methanone.(7)(2′-bromo-3′,4′-dimethoxy-6′-methylphenyl)-(2,3-dibromo-4,5-dimethoxyphenyl)-methanoneand catalyst AIBN was placed in a three-necked round bottom flask, anddissolved in CCl₄. Under hv condition, to the solution was added NBSwith stirring. Mole ratio of(2′-bromo-3′,4′-dimethoxy-6′-methylphenyl)-(2,3-dibromo-4,5-dimethoxyphenyl)-methanoneand NBS was 1:2˜1:2.5. TLC was used to monitor the reaction. Theprecipitate was filtered off and the filtrate was removed in vacuo toproduce a brownish residue. The residue was purified by chromatographyto give white solid. Spectrum analysis verified the compound is(2′-bromo-6′-(dibromomethyl)-3′,4′-dimethoxyphenyl)-(2,3-dibromo-4,5-dimethoxyphenyl)-methanone.4. Synthetic routes according to claim 2, wherein said that theprocedures of compound 2, 3, 4 and 5 are as follows: (1) Under ice bathcondition, to a stirred solution of 5,6-dibromo-veratraldehyde in MeOHwith mass concentration 15-20% was added NaBH₄. Mole ratio ofNaBH₄:5,6-dibromo-veratraldehyde was 1:4˜1:3. TLC was used to monitorthe reaction. 10% HCl was added into the reaction to acidified pH=5-6.MeOH was evaporated and the residue was extracted with CH₂Cl₂. Theorganic lay was collected, dried over anhydrous MgSO₄ and concentratedin vacuo to give white solid. Spectrum analysis verified the compound is5,6-dibromo-3,4-dimethoxy-phenyl-methanol. (2) Under ice bath condition,to a stirred solution of 5-bromo-3,4-dimethoxy-methylbenzene and5,6-dibromo-3,4-dimethoxy-phenyl-methanol in CH₂Cl₂ was added AlCl₃.Mass concentration of 5-bromo-3,4-dimethoxy-methylbenzene and5,6-dibromo-3,4-dimethoxy-phenyl-methanol were 4˜10%. Mole ratio ofAlCl₃:1-bromo-2,3-dimethoxy-5-methylbenzene:2,3-dibromo-4,5-dimethoxy-phenyl-methanolwas 1:1:1 three portions. TLC was used to monitor the reaction. Themixture was poured into ice water. The organic layer was washed with 3%HCl three times, dried over anhydrous MgSO₄ and concentrated in vacuo.The residue was recrystallized from MeOH to give white solid. Spectrumanalysis verified the compound is2,3-dibromo-1-(2′-bromo-3′,4′-dimethoxy-6′-methylbenzyl)-4,5-dimethoxybenzene. (3) Under hv condition, to a solution of AIBN or BPO and2,3-dibromo-1-(2′-bromo-3′,4′-dimethoxy-6′-methylbenzyl)-4,5-dimethoxybenzene and in CCl₄, with mass concentration 5˜10% was added NBS. Moleratio of AIBN orBPO:2,3-dibromo-1-(2′-bromo-3′,4′-dimethoxy-6′-methylbenzyl)-4,5-dimethoxybenzene=1:100 andNBS:2,3-dibromo-1-(2′-bromo-3′,4′-dimethoxy-6′-methylbenzyl)-4,5-dimethoxybenzene=1.1:1. TLC was used to monitor the reaction. Then hv stopped.The precipitate was filtered off and the solvent was removed in vacuo toproduce a brownish residue. The residue was purified by chromatographyeluted with petroleum ether:ethyl acetate=8:1 to give white solid. Thewhite solid with mass concentration 10˜15% and K₂CO₃ with massconcentration 5˜10% were dissolved in mixture of dixoane and H₂O withvolume ratio 1:1. The mixture was heated to 90-100° C. TLC was used tomonitor the reaction. The mixture was added five-fold volume of CHCl₃and H₂O. The organic lay was collected and concentrated in vacuo to givewhite solid. Spectrum analysis verified the compound is(3-bromo-2-(2′,3′-dibromo-4′,5′-dimethoxybenzyl)-4,5-dimethoxyphenyl)-methanol.(4) Under 0° C. condition, to a solution of(3-bromo-2-(2′,3′-dibromo-4′,5′-dimethoxybenzyl)-4,5-dimethoxyphenyl)-methanolin CH₂Cl₂, with mass concentration 5˜10% was added dropwise 1mol·L⁻¹BBr₃ dichloromethane solution. Mass ratio of BBr₃: compound 8 was6:1˜8:1. The reaction mixture stirred over night at room temperature.Then the mixture was poured into ice-cold water and extracted with EtOAcfor three times. The organic lay was collected, and concentrated invacuo. The residue was dissolved in n-propanol, iso-propanol, n-butylalcohol and isobutanol, respectively. Then 1-5 mL 85% H₃PO₄ was added.After refluxing for 10-12 hours, the solvent was removed in vacuo. Theresidue was purified by column chromatography to produce yellow solid3,4-dibromo-5-(2-bromo-3,4-dihydroxy-6-(propoxymethypbenzyl)benzene-1,2-diol,3,4-dibromo-5-(2-bromo-3,4-dihydroxy-6-(isopropoxymethyl)benzyl)benzene-1,2-diol,3,4-dibromo-5-(2-bromo-6-(butoxymethyl)-3,4-dihydroxybenzyl)benzene-1,2-diol,3,4-dibromo-5-(2-bromo-3,4-dihydroxy-6-(isobutoxymethyl)benzyl)benzene-1,2-diol.5. Synthetic routes according to claim 2, wherein said that theprocedures of compound 6 are as follows: (1) Under ice bath condition,to a solution of veratrole and(3-bromo-2-(2′,3′-dibromo-4′,5′-dimethoxybenzyl)-4,5-dimethoxyphenyl)-methanolin CH₂Cl₂, was added AlCl₃ with stirring. Mass concentration ofveratrole and(3-bromo-2-(2′,3′-dibromo-4′,5′-dimethoxybenzyl)-4,5-dimethoxyphenyl)-methanolwere 5-10%. Mole ratio of AlCl₃:veratrole:(3-bromo-2-(2′,3′-dibromo-4′,5′-dimethoxybenzyl)-4,5-dimethoxyphenyl)-methanolwas 1.2:1:1. TLC was used to monitor the reaction. The mixture waspoured into ice-water. The organic phase was washed with 3% HCl forthree times, then dried over anhydrous MgSO₄ and concentrated in vacuo.The residue was recrystallized from MeOH to give white solid. Spectrumanalysis verified the compound is2,3-dibromo-1-(2′-bromo-6′-(3″,4″-dimethoxybenzyl)-3′,4′-dimethoxybenzyl)-4,5-dimethoxybenzene.(2) At room temperature, to a solution of2,3-dibromo-1-(2′-bromo-6′-(3″,4″-dimethoxybenzyl)-3′,4′-dimethoxybenzyl)-4,5-dimethoxybenzenein CH₂Cl₂ was added dropwise bromine. Mole ratio of bromine:2,3-dibromo-1-(2-bromo-6′-(3″,4″-dimethoxybenzyl)-3′,4′-dimethoxybenzyl)-4,5-dimethoxybenzenewas 2:1. TLC was used to monitor the reaction. The solvent wasevaporated and the residue was redissolved in CHCl₃. The organic phasewas washed with 5% Na₂SO₃ for two times, and concentrated in vacuo. Theresidue was recrystallized in methanol to give white solid. Spectrumanalysis verified the compound is2,3-dibromo-1-(2′-bromo-6′-(2″-bromo-4″,5″-dimethoxybenzyl)-3′,4′-dimethoxybenzyl)-4,5-dimethoxybenzene.6. Application of PTP1B inhibitors according to claim 1 for treatment oftype 2 diabetes mellitus, wherein said that the PTP1B inhibitors arecompounds with PTP1B inhibitory activity. The compounds have beenimplicated in the negative regulation of insulin signal transductionpathways, enhanced insulin sensitivity and modulated blood glucose, andcould be used for treating type 2 diabetes mellitus.